There are many pathways and processes that appear to regulate the rate of aging and our susceptibility to age-related diseases such as neurodegeneration, atherosclerosis and cancer. One process that has been increasingly implicated is defects in genomic stability. Various mouse models, as well as rare human conditions, that are characterized by increased genomic instability also manifest aspects of accelerated aging. We believe that understanding the relationship between genome maintainence and aging will provide useful insights into how one could alter the susceptibility for various age-related pathologies. Our initial interest in this field came form experiments where we analyzing the ability of Brca1 deficient mouse embryonic fibroblasts to undergo premature senescence. Using a genetic approach, we wondered whether it might be possible to resuce Brca1-mediated senescence. Our analysis found that indeed the deletion of the gene 53BP1 resuced Brca1 deficient MEFs from senescence (Cao et al., Mol Cell, 2009). Suprisingly, this rescue was also seen in the whole animals as the embryonic lethality normally observed in Brca1 deficient mice was completely rescued in mice also deficient in 53BP1. Perhaps even more paradoxically, double deficient mice (Brca1/53BP1 mice) lived a near normal lifespan, with a relatively low level of tumor incidence. In a follow up study performed in the laboratory of our collaborator Andre Nussenzweig (NCI) it was demonstrated that the loss of 53BP1 can restore normal homologous recombination in Brca1 deficient cells (Bunting et al., Cell, 2010). We believe these results have promise for the development of new therapies aimed at reducing the rate of tumor formation in patients with mutant Brca1 status. We are currently using the Brca1 deficient model to further extend these analysis, with particular emphasis on other genes that might provide phenotypic rescue.